A Novel RAD51-BRCA2 Complex Stabilizing Drug: A Medical Countermeasure for Mitigating Accidental Radiation Exposure

The project focuses on developing small-molecule protein ligand interface stabilizers (SPLINTS), specifically MH analogs like MH01, to target and stabilize the BRCA2-RAD51 complex, a key component of homologous recombination (HR) for DNA double-strand break (DSB) repair. The goal is to establish MH01 as a medical countermeasure for mitigating acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). Specific aims include: 1. Optimizing the MH01 regimen for mitigating radiation toxicity by integrating pharmacokinetics, pharmacodynamics, and biophysical assays. 2. Elucidating the precise mechanism by which MH01 enhances the BRCA2-RAD51 complex's functioning during DSB repair following ionizing radiation (IR). 3. Evaluating MH01 efficacy in mitigating radiation-induced gastrointestinal tract and cardiac toxicities.